Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition that involves persistent deregulation of multiple systems within the body including the immune, endocrine and cardiovascular systems. The condition affects both women and men. However, published cohorts indicate a 60 to 80% preponderance of women. In an effort to understand the underlying mediators of dysfunction, our research group has developed a dynamic model to identify the mediators of persistence and relapse, with the primary goal of pinpointing the underlying mechanisms of the condition and targeting treatment more effectively. In this application we turn to gender differences. Utilizing this model that involves challenging a patient with exercise and drawing bloods at multiple times to map out mediators of genomic, cellular and chemical response, we propose to compare men and women with ME/CFS. Our research efforts in the related gulf war illness (GWI) have demonstrated differences between gender in regulatory dysfunction and response that make a ready and useful comparison group for this proposal. While GWI and ME/CFS present with similar symptomatology, they have quite different gene activation responses to exercise and distinct cytokine signatures, though they share common autonomic, inflammatory and cellular immune dysfunction. Areas of overlap are intriguing potential therapeutic targets, though it would not be surprising to discover quite distinct modeled therapeutic strategies based on illness (GWI vs. ME/CFS) and gender. Our previous work in males with GWI has progressed to phase 1 clinical trials, as supported by a newly awarded DoD consortium grant. The aim of the consortium is to identify signaling mechanisms relevant to GWI in male patients and outline the most promising biomarkers tied to these signaling pathways and to target pathways for intervention studies that would not only improve symptomatology but ultimately reset homeostasis. The enthusiasm for this method has resulted in funding to move this to work to include women with GWI. In addition, we are also funded through the NIH to assess differences in genomic, cellular and chemical response using our dynamic model among female patients with ME/CFS and healthy controls. The clear missing link is the comparison of men with ME/CFS to outline further differences in response between genders and develop effective tailored treatments for both men and women. We will also extend our modeling work of immune regulatory pathways and pathways that regulate latent viral expression in a way that will enable us to compare gender differences in terms illness mechanisms and explore gender-specific therapeutic targets. We aim to understand the mediators of persistence and relapse in men with ME/CFS, as we have in women. We ask in this application for the funds needed for the therapeutic target/modeling studies of men with ME/CFS with the depth required to move toward effective therapy.